Measuring the unseeable: Researchers probe proteins' 'dark energy'

July 19, 2007
Penn Researchers Probe Proteins
Artist rendering of calmodulin molecule depicting protein 'dark energy.' Credit: Mary Leonard and Michael Marlow, PhD, University of Pennsylvania School of Medicine

Researchers at the University of Pennsylvania School of Medicine are the first to observe and measure the internal motion inside proteins, or its “dark energy.” This research, appearing in the current issue of Nature has revealed how the internal motion of proteins affects their function and overturns the standard view of protein structure-function relationships, suggesting why rational drug design has been so difficult.

The situation is akin to the discussion in astrophysics in which theoreticians predict that there is dark matter, or energy, that no one has yet seen,” says senior author A. Joshua Wand, PhD, Benjamin Rush Professor of Biochemistry. “Biological theoreticians have been kicking around the idea that proteins have energy represented by internal motion, but no one can see it. We figured out how to see it and have begun to quantify the so-called ‘dark energy’ of proteins.”

Proteins are malleable in shape and internal structure, which enables them to twist and turn to bind with other proteins. “The motions that we are looking at are very small, but very fast, on the time scale of billions of movements per second,” explains Wand. “Proteins just twitch and shake.” The internal motion represents a type of energy called entropy.

Current models of protein structure and function used in research and drug design often do not account for their non-static nature. “The traditional model is almost a composite of all the different conformations a protein could take” says Wand.

The researchers measured a protein called calmodulin and its interactions with six other proteins when bound to a protein partner one at a time. These binding partners included proteins important in smooth muscle contraction and a variety of brain functions.

Using nuclear magnetic resonance spectroscopy, the investigators were able to look at the changes in the internal motion of calmodulin itself in each of the six different protein binding situations. They found a direct correlation between a change in calmodulin’s entropy –a component of its stored energy – and the total entropy change leading to the formation of the calmodulin-protein complex. Finding out the contribution from individual proteins versus the entropy, or movement, of the entire protein complex has been more difficult and has been overcome in this study. From this individual contribution they deduced that changes in the entropy of the protein are indeed important to the process of calmodulin binding its partners.

“Before these unexpected results, most researchers in our field would have predicted that entropy’s contribution to protein-protein interactions would be zero or negligible,” says Wand. “But now it’s clearly an important component of the total energy in protein binding.”

Because of this new information, the researchers suggest that the entropy component may explain why drug design fails more often than it works. Currently, drugs are designed generally based on the precise structures of their biological targets, active regions on proteins that are intended to inhibit key molecules. However, the number of designed molecules actually binding to their targets is low for many engineered molecules. “We think that this is because the design is based on a model of a static protein, not the moving, hyper protein that is constantly changing shape,” say Wand. “We need to figure out how this new information fits in and perhaps drug design could be significantly improved.”

Future directions include understanding whether the principles revealed by this study are universal and impact the thousands of protein-protein interactions that underlie biology and disease. As Wand explains, “Protein-protein interactions are central to ‘signalling’, which is often the molecular origin of diseases. Cancer, diabetes, and asthma are three important examples. We are currently looking at the role of protein entropy in the control of critical signaling events in all three.”

Source: University of Pennsylvania

Explore further: Space Kombucha in the search for life and its origin

Related Stories

Space Kombucha in the search for life and its origin

July 30, 2015

You might know it as a drink for hipsters or as an ancient brew drunk for centuries in Eurasia, but the culture that ferments sugary tea into Kombucha is going around the world. Bolted to the outside of the International ...

Head and body lice read DNA differently

July 28, 2015

What makes head lice different from body lice had scientists scratching their heads as previous genetic studies failed to find any substantial differences between the two types of lice.

Why do mitochondria retain their own genome?

July 24, 2015

It sounds like science fiction to suggest that every cell in the human body is occupied by a tiny genome-equipped organelle, with which we exist in symbiosis. But in actuality, eukaryotic life is dependent on mitochondria, ...

RNA insecticide could target specific pests

July 21, 2015

A novel insecticide targets a specific gene in a pest, killing only that bug species on crops and avoiding collateral damage to beneficial insects caused by today's pesticides.

Recommended for you

How bees naturally vaccinate their babies

July 31, 2015

When it comes to vaccinating their babies, bees don't have a choice—they naturally immunize their offspring against specific diseases found in their environments. And now for the first time, scientists have discovered how ...

Image: Hubble sees a dying star's final moments

July 31, 2015

A dying star's final moments are captured in this image from the NASA/ESA Hubble Space Telescope. The death throes of this star may only last mere moments on a cosmological timescale, but this star's demise is still quite ...

Exoplanets 20/20: Looking back to the future

July 31, 2015

Geoff Marcy remembers the hair standing up on the back of his neck. Paul Butler remembers being dead tired. The two men had just made history: the first confirmation of a planet orbiting another star.

Earth flyby of 'space peanut' captured in new video

July 31, 2015

NASA scientists have used two giant, Earth-based radio telescopes to bounce radar signals off a passing asteroid and produce images of the peanut-shaped body as it approached close to Earth this past weekend.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.